Synthetic programs are continuing to develop new ligands for imaging brain drug receptors by positron emission tomography (PET) and single photon emission computed tomography (SPECT) scanning, and the NIH Opiate Total Synthesis is employed to provide previously inaccessible unnatural enantiomers of opiates and derivatives. The binding characteristics, pharmacology, immuno-chemistry, and the multiplicity of opioid receptors were examined, and new drugs were explored as treatment agents for cocaine abuse and for their interaction with the dopamine transporter. Multiple delta opioid receptors - Nonpeptide opioid receptor ligands with a remarkable 2000 fold binding selectivity for the delta vs mu subtype were synthesized. These compounds are being evaluated in vivo and in vitro. Second generation ligands, which are expected to be extremely valuable probes for further elucidation of the function of the delta receptor subtypes, are being synthesized as affinity labels, tritiated probes and as agents for PET and SPECT imaging of brain delta receptor subtypes in living animals and humans. Such studies will include quantitation of density (Binax) and affinity (Kd) of this receptor subpopulation in normal subjects and subjects with various disorders involving dysfunction of the opioid receptor endorphin system. Immunoregulatory opioids - Our studies indicate that opioid-induced immunosuppression is mediated primarily through central mu receptors. DAGO (60 nmol) had no effect on plasma corticosterone or ACTH levels, suggesting that central mu binding does not reduce NK activity through activity through activation of the hypothalamic-pituitary-adrenal-axis. Potential agents for treatment and prevention of cocaine abuse -Ligand binding and pharmacological studies have revealed two different binding sites for dopamine (DA) uptake inhibitors in the rat caudate nucleus. Synthetic studies have continued toward identification of drugs which will be useful in the treatment and prevention of cocaine abuse are continuing.